Three's company: With Amvuttra approval, Alynlam joins Pfizer, BridgeBio in the ATTR-CM ring

The FDA on Thursday approved Alnylam's RNAi therapeutic a few days ahead of schedule, giving Amvuttra (vutrisiran) a green light to treat transthyretin-mediated amyloid cardiomyopathy (ATTR-CM). The therapy's potential to change the ATTR-CM treatment landscape earned it a place on FirstWord's list of drugs that will shape 2025.

Amvuttra is now the second drug — and first with a wholly unique mechanism of action — to challenge Pfizer's Vyndaqel/Vyndamax (tafamidis), which had been the sole ATTR-CM treatment option for about five years until the November 2024 approval of BridgeBio's Attruby (acoramidis). To make up for BridgeBio's headstart, Alnylam had cashed in a priority review voucher to ensure a speedy review of Amvuttra.

Like Vyndaqel, Attruby is an oral TTR stabiliser, whereas Amvuttra is an RNAi therapeutic that delivers rapid knockdown of TTR. It was first approved for polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) in 2022. 

Initially greenlit in 2019, the Vyndaqel family has proved to be particularly lucrative for Pfizer. The products brought in a total of $5.5 billion in global sales last year, up 60% from 2023 revenues of $3.3 billion.

Alynylam is hoping to capitalise on that fast-growing ATTR-CM market, as Amvuttra already sits on the cusp of blockbuster status. The RNAi therapeutic brought in $970 million in sales last year from its hATTR-PN indication; following its label expansion Thursday, the pharma projected full-year 2025 revenue between $1.6 billion and $1.7 billion for its TTR portfolio, which also includes Onpattro (patisiran).

Given as four subcutaneous doses per year, Amvuttra's current hATTR-PN wholesale acquisition cost of $119,000 per prefilled syringe will remain the same for ATTR-CM.

Newcomer showdown

Amvuttra will now go head-to-head with Attruby to wrestle away a piece of Pfizer's ATTR-CM pie.

A series of physician polls conducted by FirstWord last year showed that cardiologists view Amvuttra as an important new treatment option, but whether it, or Attruby, offers the biggest benefit to patients depends on different interpretations of available clinical data. For related analysis, see Physician Views Results: Cardiologists have much to ponder with ATTR-CM treatment options set to expand; Physician Views Poll Results: Amvuttra another compelling treatment option for ATTR-CM, say majority of cardiologists; and Physician Views Results: Cardiologist feedback suggests Alnylam well placed to take on Pfizer in ATTR-CM field.

Thursday's approval was based on the results of the Phase III HELIOS-B trial, in which Amvuttra achieved statistical significance compared to placebo on all 10 pre-specified primary and secondary endpoints.

Specifically, the RNAi therapeutic reduced the composite endpoint of all-cause mortality (ACM) and recurrent cardiovascular (CV) events by 28% compared to placebo after 36 months. In addition, Amvuttra reduced ACM by 36% in the overall population at up to 42 months and by 35% in those not on tafamidis at baseline.

Attruby earned its clearance on the back of data from the ATTRibute-CM Phase III trial, in which the drug saw a 25% reduction in ACM and a 50% decrease in CV-related hospitalisations at 30 months.